Methods for combatting bacteria and fungi using bisdiphenylaminomethanes

ABSTRACT

CHEMICALS CONTAINING TWO DIPHENYLAMINOMETHANE GROUPS, LINKED TOGETHER BY A MOIETY OTHER THAN OXYGEN, E.G., 1,2-BIS(4-(3-METHYL-ALPHA - AMINOBENZYL)PHENOXY) ETHANE, ARE EFFECTIVE ANTIMICROBIAL AGENTS USEFUL AS AGRICULTURAL OR INDUSTRIAL FUNGICIDES AND BACTERICIDES.

United States Patent 3,808,316 METHODS FOR COMBA'I'IING BACTERIA ANDFUNGI USING BISDIPHENYLAMINOMETHANES Bogislav von Schmeling, Hamden,Conn., and Walter R. Boos, Guelph, Ontario, Canada, assignors toUniroyal, Inc., New York, N.Y., and Uniroyal Ltd., Montreal, Quebec,Canada No Drawing. Filed Mar. 2, 1972, Ser. No. 231,385 Int. Cl. A01n9/20, 9/22, 9/28 US. Cl. 424-330 9 Claims ABSTRACT OF THE DISCLOSUREChemicals containing two diphenylaminomethane groups, linked together bya moiety other than oxygen, e.g., 1,2-bis[4-(3-methyl-a1phaaminobenzyDphenoxy] ethane, are effective antimicrobial agents useful asagri cultural or industrial fungicides and bactericides.

This invention relates to new chemicals which contain twodiphenylaminomethyl groups linked together by a moiety other thanoxygen, and to a method of controlling microbes with such chemicals.

In our copending application Ser. No. 861,153, filed Sept. 25, 1969, nowUS. Pat. 3,663,712, issued May 16, 1972, control of microbes with4,4-bis(alpha-aminobenzyl) diphenyl ethers is disclosed.

The present invention is directed to chemicals which arebisdiphenylaminomethanes, wherein two diphenylaminomethane groups arelinked together by a moiety other than oxygen or have a phenyl or othercyclic radical in common, as represented for example by chemicals of thefollowing Formulas I or II:

wherein X represents a connecting moiety selected for instance from thegroup consisting of -O(CHz)nO-- (wherein n is, e.g., 2 to 4),

and furyl fused to one phenyl group of each diphenylaminomethane moiety,X represents phenylene or pyridinediyl, R and R are the same ordifferent and are hydrogen or various substituents such as hydrocarbyl(e.g., alkyl, preferably lower alkyl as in methyl) or nonhydrocarbyl(e.g., alkoxy, as in such lower alkoxys as methoxy, or aryloxy as inphenoxy, etc.), and a, b, c and d are usually 1 or 2 (preferably 1).

Thus, exemplary chemicals are those in which the linking group is O(CHO- as in the structures:

NH: I O CHM 1'1 J, ChemicalA o CHzCHz0- it L Chemical B 3,808,316Patented Apr. 30, 1974 NH: -h OCH:CHO

k CH: J2 ChemicalC NH: I: -ooH,cHoHon J, ChemicalD NH; I awamrwrcma J2ChemicalE or amino (e.g., NH-, NCH etc.) as in the structures:

NH: 1 J2 Chemical F H J: Chemical G or S or SO as in the structures:

NH: III in Chemical H EH2 Id J1 Chemical I NH: 1 J2 Chemical] or --CH orCHNH as in the structures:

NH: J

H 2 Chemical K NH: H .12 Chemical L or phenyl group as in thestructures:

E 1 1i AU-Gig le NH: NH:

it it Chemical N NH: NH: cmo@-o--e 0cm I l 1 Chemical 0 NH: NH! 7 J ocm1i Chemical P Chemical Q,

or heterocyclic ring as in the structures:

CH: CH:

NH, NH, l 1'1 1 1 Chemical R H Chemical 8 Chemical '1 Preferredchemicals are as follows:

Chemical B: 1,2-bis[4-(3-methyl-alpha-aminobenzyl)phenoxylethane.

Chemical D: 1,3-bis[4- (alpha-aminobenzyl)phenoxy1propane.

Chemical E: 1,4-bis[4-(alpha-aminobenzyl)phenoxy1butane.

Chemical H: 4,4'-thiobis(alpha-phenylbenzylamine).

Chemical K: 4,4'-bis(alpha amino alpha phenyltolyl) methane.

In one .aspect the invention involves applying to a locus, subject toattack by microbes, a chemical of the kind described.

The invention makes possible the control, in vivo or in vitro, of suchmicroorganisms as bacteria or fungi, whether in agricultural uses, ornon-agricultural uses such as the protection of fuel oil, fabrics, etc.,from injury by microbes. Agricultural uses include the control ofvegetable and fruit diseases such as the bacterial blights and leafspots.

One method of preparing chemicals of the invention is represented by theequations:

NOH R In this method, hereinafter called Method 1, an appropriatestarting Compound III having two phenyl groups linked together by amoiety other than oxygen is subjected to a Friedel-Crafts reaction withan aromatic acid chloride IV to form a diketone V. The diketone V may beconverted, by reaction with hydroxylamine hydrochloride, into thecorresponding dioxime VI, which may in turn be converted into thedesired diamine I by catalytic hydrogenation.

A second method of preparing chemicals of the invention, hereinafterreferred to as Method 2, is represented by the equations:

R l i ll HNCH (VII) R Hydrolysis R 1TH: NH: R

H R R H In Method 2, an aromatic diketone V is converted by a Leuckartreaction, into the corresponding bisformamide VII, which may in turn behydrolyzed to the desired amine I by acid hydrolysis followed bytreatment with a base.

A third method of preparation (Method 3) is represented by theequations:

COCl

AlCh 0 0 0 II [I HONHrHCl In Method 3 an appropriate aromatic diaciddichloride VIII is converted by a Friedel-Crafts reaction with anappropriate aromatic Compound IX, to a diketone X. The diketone X inturn may be converted by reaction with hydroxylamine hydrochloride tothe corresponding dioxime XI, which may be reduced to the desireddiamine II by catalytic hydrogenation.

It can be seen from the structures of the diamines I and H that theyhave two centers of asymmetry and that compounds prepared by the abovemethods are a mixture of several stereoisomers. These are not readilyseparable by crystallization or otherwise.

The chemicals employed in this invention possess a high degree ofbactericidal activity controlling such bacteria as Pseudomonasaeruginosa (Schroeter) Migula, Escherichia coli (Migula) Castellani andChalmers, Staphylococcus aureus Rosenbach, Desulfovibrio desalfuricans(Beijerinck) Kluyver and van Niel, Streptococcus pyogens Rosenbach,Xanthomonas phaseoli (Smith) Dowson and Erwinz'a amylovora (Burrill)Winslow et al.

The chemicals employed in this invention also control fungi such asAlternaria solani (Ellis and Mastin) Sorauer, Cladosporium resinae f.resinae de Vries, Hormodendrum spp., Chaetomium globosum Kunz ex Fries,Aurobasidum (Pullularia) pullulans (de Bary and Lowe) Berkhout, Candidaalbicans (Robin) Berkhout, Trichophyton mentagrophytes (Robin) Blanchardand Uromyces phaseoli typica Arth.

In agricultural applications, the chemical may be applied directly toplants (e.g., seeds, foliage) or to soil in which plant life is growingor is to be grown, to protect the plant life against the harmful effectsof such pathogenic microbes as bacteria and fungi. For example, thechemical may be applied to seeds by tumbling the chemical with theseeds, either alone or in admixture with a powdered solid carrier, tocoat the seeds. Typical powdered solid carriers are the various mineralsilicates, e.g., mica, talc, pyrophyllite, and clays. The chemical mayalso be applied to the seeds in admixture with a conventionalsurface-active wetting agent, with or without additional powdered solidcarrier, as by first Wetting the mixture with a small amount of waterand then tumbling the seeds in the slurry. The surface-active wettingagents that may be used with the chemical may be any of the conventionalanionic, non-ionic, or cationic surface-active agents. Suchsurface-active agents are well known and reference is made to US. Pat.No. 2,547,724, columns 3 and 4, for detailed examples of the same. As aseed protectant, the amount of the chemical coated on the seeds will be/1 to 12 ounces per hundred pounds of the seed. As a soil treatment forfungi and the like, the chemical may be applied as a dust in admixturewith sand or soil or a powdered solid carrier such as a mineralsilicate, with or without an additional surface-active wetting agent, tothe furrows with the planting of seeds, or the chemical may be appliedas an aqueous spray, if desired including a surface-active dispersingagent, or a surface-active dispersing agent and a powdered solidcarrier, to the seed rows before, or with, or after planting the seeds.As a soil treatment, the amount of the chemical applied to the seed rowswill be from 0.1 to pounds per acre applied to the seed rows based onrows 2" wide and 2" deep a distance of 40 apart. Also, as a soiltreatment, the chemical may be applied broadcast as a similar dust oraqueous spray with an application rate of 1.0 to 100 pounds per acre. Asa foliage treatment (e.g., fungicidal or bactericidal), the chemical maybe applied to growing plants at a rate of A to 10 pounds per acre. Suchapplication is generally as an aqueous spray which also contains asurface-active dispersing agent, with or without a powdered solidcarrier or a hydrocarbon solvent. These sprays usually are repeated attime intervals ranging from three days to two weeks during the growingseason. Typical formulations are as follows:

. 6 (a) Emulsiiiable concentrate Percent Bis(diphenylaminomethane)chemical 48.1

Surfactant (e.g., Tween polyoxyethylene sor- 1 Alkylaryl polyetheralcohol, 9-10 moles polyethylene oxide, in dry powdered form (40% activeon an insoluble carrier). The active ingredient in Triton X- is TritonX-100, which is a liquid 'nonionic surfactant(isooctylphenylpolyethoxyetlilanol, obtained by condensing thealkylphenol with ethylene l hlymerized sodium salts of alkylnaphthalenesulfonic acid (more particularly, the sodium salts of dinaphthylmethanesulfonic acids obtained from naphthalene, sulfuric acid andformaldehyde, according to U.S. Pat. 1,336,759, Schmidt, Apr. 13, 1920).

As industrial bactericides and fungicides, the present chemicals may beused to control bacteria or fungi by contacting the bacteria or fungiwith the chemical in any suitable manner. Materials capable ofnourishing bacteria and fungi may be protected from destruction by suchpests by contacting, mixing, or impregnating with the chemical. Suchmaterials include petroleum oils, fuel oils, fabrics, cellulosicmaterials in various forms including textiles, wood, paper, etc. Inorder to broaden their spectrum or increase their effect, the chemicalsmay be combined with other pesticidal control agents such as fungicides,bactericides, insecticides or miticides.

Chemicals of this invention may be used as antimicrobial agents for thepreservative of petroleum hydrocarbons. Petroleum hydrocarbons are knownto be utilized by bacteria and fungi as a food source. The resultingincrease in microbial population can cause various problems such asfilter plugging, metal corrosion of storage tanks and aircraft fueltanks, fuel line plugging and flame-outs. A biocide added to hydrocarbonfuels can prevent microbial growth and eliminate the problems mentioned.

Chemicals of this invention may be used as material preservativesagainst cellulose-degrading fungi causing deterioration of textiles,paper, wood, etc.

The chemicals of the invention may be incorporated in soap to be used incombatting bacteria and fungi.

Equivalent to the chemicals per se in many cases are the salts thereof(e.g., hydrochlorides, acetates, citrates), which are readily providedby treatment with an appropriate acid.

The following examples, in which all quantities are expressed by weightunless otherwise indicated, will serve to illustrate the practice of theinvention in more detail.

EXAMPLE 1 This example uses Method 1 to prepare Chemical B, 1,2bis[4-(3-methyl-alpha-aminobenzyl)phenoxy] ethane.

Step 1: Preparation of 1,2-bis[4-(3-methylbenzoyl)phenox'y]ethane.-To astirred suspension of anhydrous aluminum chloride (24 g.) in 300 ml. dry1,2-dichloroethane was added 1,2-diphenoxyethane (17.8 g., .083 mole) atroom temperature. To this mixture was added over a period of 30 minutesm-toluoyl chloride (27 g., 0.166 mole). The temperature of the reactionrose to 40 (all temperatures are centigrade) and hydrogen chloride gasevolved from the mixture. Following the addition of the m-toluoylchloride the reaction was externally heated to 65 plus or minus 3". Thistemperature and stirring were maintained for 22 hours. The mixture wasthen allowed to cool to room temperature and poured on 1 kg. of

crushed ice to destroy the aluminum chloride complex. The ice wasallowed to melt and the water separated from the organic layer. Thelatter was washed twice with 200 ml. of 10% hydrochloric acid, threetimes with water and the solvent removed by distillation. The residualcrude crystals were recrystallized from dichloroethane, yield 15.9 g.(42.5%) M.P. 164 167".

Calculated for G l-I (percent): C, 79.98; H, 5.82. Found (percent): C,79,65; H, 5.88.

Step 2: Preparation of 1,2-bis[4-(3-methylbenozyl)phenox'y]ethanedioxime.-A mixture of 1,2-bis[4-(3-methylbenzoyl)phenoxy]ethane (13.5g., 0.03 mole), hydroxylamine hydrochloride (8.3 g., 0.1 mole), hydratedsodium acetate ('18 g., 0.13 mole) and 300 ml. ethyl alcohol was heatedto gentle reflux for 24 hours, then added to 1.5 1. water and allowed tostand for 18 hours. The resulting crystals were filtered, washed withwater, dried first at room temperature then in an oven at 90 for 5hours. The yield of the oxime was 12.3 g. (85.4% of theory) M.P.151-153.

Calculated for C H N O (percent): C, 74.98; H, 5.87; N, 5.83. Found(percent): C, 74.75; H, 6.01; N, 5.36.

Step 3: Preparation of 1,2-bis[4-(3-methyl-alphaaminobenzyl)phenoxy]ethane.A reaction mixture was preparedfrom 1,2-bis[4(3-methylbenzoyl)phenoxy]ethane dioxime (10.6 g., .022mole), 400 ml. absolute ethyl alcohol saturated with ammonia gas andRaney nickel catalyst W-6 (2 g.). This mixture was subjected to 500p.s.i. hydrogen pressure, heated to 90 and stirred for 7 hours. TheRaney nickel was removed by filtration and the alcohol and ammonia bydistillation. The residual crude material was crystallized from ethanolto yield 4.2 g. (41.9%) of material M.P. '113--ll5.

Calculated for C H N O (percent): C, 79.61; H, 7.13; N, 6.19. Found(percent): C, 79.36; H, 7.27; N, 5.80.

The infrared spectrum of the product indicates absence of ketone groups(i.e., the intermediate) and presence of amine groups.

EXAMPLE 2 This example illustrates the preparation of Chemical E, 1,4bis[4-(alpha-aminobenzyl)phenoxy]-butane, by Method 1, from1,4-diphenoxy-n-butane and benzoyl chloride. The procedure of Example 1was followed.

Step 1: 1,4-bis(4-benzoylphenoxy)butane (V). 1,4-diphenoxybutane (III,24.2 g.) and benzoyl chloride (IV, 29 g.) were reacted in 250 ml. of1,2-dichloroethane in the presence of aluminum chloride (28 g.) for fourhours at 60 to yield 18.3 g. (41% of theory) of colorless crystals, M.P.l63-4.

Calculated for C H O (percent): C, 79.98; H, 5.82. Found (percent): C,80.16; H, 5.98.

Step 2: 1,4 bis(4 benzoylphenoxy)butane dioxime. (VI). The diketone Vfrom Step 1 (13.5 g.), hydroxylamine hydrochloride (7 g.) and sodiumacetate (15 g.) were refluxed in a mixture of ethyl alcohol (250 ml.)and dioxane (125 ml.) for sixteen hours to yield 6.3 g. (43.6% ortheory) of colorless crystals, M.P. l54-6.

Step 3: 1,4 bis [4 (alpha-aminobenzyl)phenoxy]butane (E). The dioxime VIfrom Step 2 (6.3 g.) was dissolved in ethyl alcohol saturated withammonia gas (220 ml.) and Raney nickel W-6 (2.3 g.) added. The mixturewas subjected to 650 p.s.i. hydrogen pressure and heated to 90 fortwenty-two hours. The catalyst was removed by filtration and the solventwas removed by distillation to yield 4.1 g. (69.2% of theory) ofcolorless crystals, M.P. 1203.

Calculated for C H N O (percent): C, 79.61; H, 7.13; N, 6.19. Found(percent): C, 79.47; H, 7.35; N, 6.79.

EXAMPLE 3 Using Method 1, Chemical D,1,3-bis[4-(alpha-aminobenzyl)phenoxy]propane, was prepared from1,3-diphe noxy-n-propane and benzoyl chloride following the procedure ofExample 1.

Step 1: 1,3bis(4 benzoylphenoxy)propane (V). 1,3- diphenoxypropane (III,22.8 g.), benzoyl chloride (IV, 31 g.) and anhydrous aluminum chloride(33 g.) were reacted in 1,2-dichloroethane (300 ml.) for eighteen hoursat 70 to yield 33.4 g. (76.6% of theory) of colorless crystals, M.P.1468.

Step 2: 1,3-bis(4 benzoylphenoxy)propane dioxime (VI). The diketone Vfrom Step 1 (26.2 g.), hydroxylamine hydrochloride, (16.7 g.) and sodiumacetate (36 g.) were refluxed in a mixture of 350 cc. of ethyl alcoholand 350 cc. of dioxane for twenty-five hours to yield 27.5 g. (98.2% oftheory) of colorless crystals, M.P. 2058.

Step 3: (1,3-bis(4 alpha-aminobenzyl)phenoxy]propane (D). The dioxime VIfrom Step 2 (20 g.) was dissolved in ethyl alcohol saturated withammonia gas (220 ml.) and Raney nickel W-6 (2 g.) added. The mixture wassubjected to 500 p.s.i. hydrogen pressure and heated at for four hours.The catalyst was removed by filtration and the solvent was removed bydistillation to yield 15.5 g. (82.5% of theory) of pale yellow crystals,M.P. 1189.

Calculated for C H N O (percent): C, 79.42; H, 6.90; N, 6.39. Found(percent): C, 79.14; H, 6.57; N, 6.89.

EXAMPLE 4 Using Method 1, Chemical A,1,2-bis[4-alpha-aminobenzyl)phenoxy]ethane, was prepared by theprocedure of Example 1, from 1,2-diphenoxyethane and benzoyl chloride;product M.P. 116-120.

Calculated for C H N O (percent): C, 79.21; H, 6.65; N, 6.60. Found(percent): C, 79.29; H, 6.52; N, 6.39.

EXAMPLE 5 Using Method 1, and following the procedure of Example l,Chemical K, 4,4-bis(alpha-amino-alpha-phenyltolyl)methane, was preparedfrom diphenylmethane and benzoyl chloride.

Step 1: 4,4-dibenzoyldiphenylmethane (V). (Preparation of this chemicalwas reported by G. Wittig et al. Ber. 61, p. 858.) Diphenylmethane (III,84 g.) and benzoylchloride (IV, 147 g.) were reacted in the presence ofaluminum chloride (147.5 g.) in 1,2-dichloroethane (400 ml.) foreighteen hours at 20. Yield 22 g. (12% of theory) of yellow crystals,M.P. 1414.

Step 2: 4,4-dibenzoyldiphenylmethane dioxime (VI). The diketone V fromStep 1 (16 g.), hydroxyla'mine hydrochloride (7 g.) and sodium acetate(14 g.) were refluxed in ethyl alcohol (300 ml.) for eleven hours. Thereaction mixture was added to 1 l. of water yielding 17 g. (98% oftheory) pale yellow crystals, M.P. 2102.

Step 3: 4,4 bis(alpha-amino-alpha-phenyltolyl)methane (K). The dioximeVI from Step 2 (17 g.) was dissolved in ethyl alcohol (225 ml.)saturated with ammonia gas and Raney nickel W-6 (2.3 g.) added. Themixture was subjected to 650 p.s.i. hydrogen pressure and heated at forsix hours. The catalyst was removed by filtration and ml. of solvent bydistillation. The yellowbrown precipitate was filtered and dried. Yield13 g. (82% of theory), M.P. 94-8.

Calculated for C H N (percent): C, 85.67; H, 6.92; N, 7.40. Found(percent): C, 85.60; H, 6.82; N, 6.91.

EXAMPLE 6 1,2 bis[4 alpha-aminobenzyl)3-methoxyphenoxy]- ethane,Chemical C, was prepared from 1,2-bis(3-methoxy-phenoxy)ethane andbenzoyl chloride, using the procedure of Example 1, Method 1. Thestructure was confirmed by infrared analysis, which indicated absence ofketone groups (i.e., intermediate) and presence of amine groups(product).

EXAMPLE 7 4,4 bis(alpha-aminobenzyl)diphenylamine, Chemical F, wasprepared from diphenylamine and benzoyl chloride, using the procedure ofExample 1, Method 1. The

structure was confirmed by infrared analysis, which indicated absence ofketone groups (i.e., intermediate) and presence of amine groups(product).

EXAMPLE 8 4,4 bis(alpha-aminobenzyl)N-methyldiphenylamine, Chemical G,was prepared from diphenylmethylamine, and benzoyl chloride, using theprocedure of Example 1, Method 1. The diamine dihydrochloride melted at202- 210"; its structure was confirmed by infrared analysis whichindicated absence of ketone groups (i.e., intermediate) and presence ofamine groups (product).

EXAMPLE 9 4,4 thiobis [alpha (3 methylphenyDbenzylamine], Chemical I,was prepared from diphenyl sulfide and mtoluoyl chloride, using theprocedure of Example 1, Method 1. The structure was confirmed byinfrared analysis which indicated absence of ketone groups (i.e.,intermediate) and presence of amine groups (product).

EXAMPLE 10 1,l-bis(alpha-amino-alpha-phenyl-p-tolyl)methylamine,Chemical L, was prepared as follows.

Step 1: 4,4'-dibenzoylbenzophenone (V) was prepared by oxidation of4,4'-dibenzoyldiphenylmethane (Chemical K, Step 1, 4.4 g.) with chromiumtrioxide (4.7 g.) by refluxing for four hours in 100 ml. glacial aceticacid. Acetic acid was removed by distillation and the crude productrecrystallized from ethyl alcohol, yield 2.9 g. (65% of theory) M.P.224-8 [reported by E. Connerade, Bull. soc. chim. Belg. 44, pp. 4l1-24(1935)].

Step 2: 4,4-dibenzoylbenzophenone trioxime (VI). The triketone V fromStep I (2.9 g.), hydroxylamine hydrochloride (3.1 g.) and sodium acetate(3.6 g.) were suspended in n-butyl alcohol (125 ml.) and refluxed fortwenty-three hours. The butyl alcohol was removed by distillation andthe crude crystals were suspended in ethyl alcohol (100 ml.) and addedto 600 ml. of water. A colorless crystalline material was collected byfiltration, dried, to yield 3 g. (93% of theory) M.P. 224-5 Step 3:1,l-bis(alpha-amino-alpha-phenyltolyl)methylamine (L). The trioxime VIfrom Step 2 (3 g.) was dissolved in ethyl alcohol (250 ml.) saturatedwith ammonia gas and Raney nickel W-6 (2 g.) added. The mixture wassubjected to 500 p.s.i. hydrogen pressure and heated to 90 for twohours. The catalyst was removed by filtration and 250 ml. of solvent wasremoved by distillation. A pale yellow crystalline material was filteredand dried. Yield 2.5 g. (92.2% of theory) M.P. 182-5".

Calculated for C27H27N3 (percent): C, 82.4; H, 6.92; N, 10.68. Found(percent): C, 82.41; H, 6.95; N, 10.70.

EXAMPLE 11 Chemical R, 2,8 bis(S-methyI-aIpha-aminobenzyl)dibenzofuran,was prepared by Method 2, as follows:

Step 1: 2,8-bis(3-met-hylbenzoyl) dibenzofuran (V) was preparedaccording to the procedure of Step 1, Example 1, dibenzofuran (42 g.,0.25 mole), m-toluoyl chloride (82 g., 0.55 mole), and anhydrousaluminum chloride (73 g., 0.55 mole) were reacted in carbon disulfide(250 ml.) for twenty-four hours at 20. The desired compound was obtainedafter recrystallization of the crude product from toluene, yield 22 g.(23% of theory), M.P. 1801.

Calculated for C H O (percent): C, 83.15; H, 4.98. Found (percent): C,83.21; H, 5.08.

Step 2: 2,8-bis [alpha-(N formyl)amino-3-methylbenzyl] dibenzofuran(VII). The above diketone (V) (16 g.) together with formamide (40 g.)and 90% formic acid 10 (12 g.) were heated for twenty hours at 170. Bythis time a colorless precipitate had formed which was not isolated, butsubjected directly to acid hydrolysis as described in Step 3.

Step 3: 2,8 bis(alpha-amino-3-methylbenzyl) dibenzofuran (R). Thereaction product (VII) of Step 2 was added to 150 ml. ethyl alcohol plus20 ml. water and 30 ml. hydrochloric acid (37%). The mixture was heatedto for two hours by which time a clear solution of the diaminedihydrochloride was obtained. The ethyl a1- cohol was removed bydistillation, 200 ml. water added followed by suflicient solid sodiumhydroxide to render the solution basic. The diamine was isolated byextraction with benzene, yield 11 g. (69% of theory) of an ambermaterial of high viscosity. This was identified as the dihydrochlorideof (R), M.P. 293-300 C.

Calculated for C H Cl N O (percent): C, 70.15; H, 5.85; N, 5.85. Found(percent): C, 69.94; H, 5.96; N, 5.94.

EXAMPLE 12 Chemical H, 4,4-thiobis(alpha phenylbenzylamine), wasprepared by Method 2.

Step 1: 4,4'-thiobis(benzophenone) was prepared in a similar manner toStep 1, Example 1. Preparation of this chemical has been reported byDilthey et al., I. prakt. Chem. 124, 114 (1930) from diphenyl sulfideg.), benzoyl chloride (134 g.) and aluminum chloride (134 g.) in 400 ml.of dichloroethane. Reaction temperature was 65 with external heating.Reaction time was three hours. Yield 122 g. (67.7% of theory) yellowcrystals, M.P. 163-4".

Calculated for C H O S (percent): C, 79.17; H, 4.6. Found (percent): C,79.38; H, 4.91.

Step 2: 4,4-thiobis [alpha phenylbenzylamine(N-formyl)] was prepared inmuch the same way as was Chemical R, Step 2, Example 11, diketone (5 g.)from Step 1, formamide (30 g.), and formic acid (4 g.) were heated at170 for sixteen hours. The resulting compound was not isolated butsubjected directly to acid hydrolysis as described in Step 3.

Step 3: 4,4'-thiobis(alpha phenylbenzylamine) (H). The reaction productof Step 2 was added to ml. of water causing separation into two layers.The organic layer was extracted with chloroform which was removed bydistillation. To the residue was added 20 ml. ethyl alcohol, 5 ml. 37%hydrochloric acid and 5 ml. water. This mixture was heated to 80 forthree hours. After cooling, enough acetone was added to the mixture tocause the diamine dihydrochloride to precipitate. This was filtered'anddried, yield 5.7 g. (92% of theory) colorless crystals, M.P. 291-4.

Calculated for C H Cl N S (percent): C, 66.51; H, 5.58; N, 5.96. Found(percent): C, 66.19; H, 5.76; N, 5.70.

This dihydrochloride can be converted to the corresponding diamine bytreatment with a base.

EXAMPLE 13 4,4-bis (alpha-amino-alpha-phenyltolyl) sulfone, Chemical J,was prepared from diphenyl sulfide and benzoyl chloride. The sulfideprepared as in Step 1 of Example 12 was oxidized to the sulfone asfollows: The diketone (5 g., H. Step 1) was dissolved in glacial aceticacid (300 ml.), 32% hydrogen peroxide (3.2 ml.) added and the mixtureheated for 5 hours at 90. The precipitate formed on addition of thereaction mixture to water (two litres) was filtered and dried, yield 5.2g. (96% of theory), M.P. 196197.

The structure of the final product, obtained by the procedure of Method1, was confirmed by infrared analysis which indicated the absence ofketone groups (i.e., intermediate) and presence of amine groups(product).

1 1 EXAMPLE 14 Using Method 3, Chemical M,1,4-bis(alpha-aminobenzyl)benzene was prepared as follows:

Step 1: 1,4dibenzoylbenzene (X) was prepared essentially as described byNoelting and Kohn, Ber. 19, page 147. Terephthaloyl dichloride (VIII)(20.3 g., 0.1 mole) was dissolved in benzene (IX) (350 ml.) andanhydrous aluminum chloride (30 g., 0.11 mole) was added. The mixturewas heated at70 for seven hours, cooled to 20 and maintained at thistemperature for eighteen hours with continual stirring. The reactionmixture was then added to 1 l. crushed ice and 20 cc. 37% hydrochloricacid. The benzene solution was washed three times with water and twicewith sodium bicarbonate solution. The excess benzene was removed bydistillation. The resulting crystalline material was recrystallized fromdimethylformamide, yield 22 g. (75.8% of theory) white crystals, M.P.158-9".

Step 2: 1,4-dibenzoylbenzene dioxime (XI). The diketone X from Step 1(26 g.), hydroxylamine hydrochloride (14 g.), and sodium acetate (18 g.)were refluxed in ethyl alcohol (500 ml.) for twenty hours. Theprecipitate formed on the addition of water (one liter) was filtered,washed with water and dried, yield 28 g. (91.3% of theory) of colorlesscrystals, M.P. 230-3". (Reported previously "by Muenchmeyer, Ber. 19,1847 (1886).)

Step 3: 1,4-bis(alpha-aminobenzyDbenzene (M) (II). The dioxime XI fromStep 2 (30 g.) was dissolved in ethyl alcohol (300 ml.), saturated withammonia gas and Raney nickel catalyst W-6 (2 g.) added. The mixture wassubjected to 700 psi. hydrogen pressure and heated at 70 for threehours. The catalyst was removed by filtration and 220 ml. of ethanol wasremoved by distillation. The pale yellow precipitate was filtered anddried. Yield 28 g. (91% of theory) M.P. 123-7".

Calculated for C H N (percent): C, 83.29; H, 6.99; N, 9.71. Found(percent): C, 83.07; H, 6.89; N, 9.59.

EXAMPLE 15 Using Method 3, Chemical N,1,3-bis(alpha-aminobenzy1)benzene, was prepared from isophthaloyldichloride and benzene; its structure was confirmed by infraredanalysis.

EXAMPLE 16 Using Method 3, Chemical 0,1,4-bis(4-methoxy-alphaaminobenzyl)benzene, was prepared fromterephthaloyl dichloride and anisole; its structure was confirmed byinfrared analysis.

EXAMPLE 17 1,3-bis(4-methoXy-alpha-aminobenzyl)benzene, Chemical P, wasprepared from isophthaloyl dichloride and anisole according to Method 3.M.P. of the diamine dihydrochloride was 212-215; its structure wasconfirmed by infrared analysis.

EXAMPLE 18 Terephthaloyl dichloride and phenoxybenzene were used toprepare 1,4 bis(4-phenoxy-alpha-amino-benzyl)benzene, Chemical Q, byMethod 3. Structure was confirmed by infrared analysis.

EXAMPLE 19 Method 3 was used to prepare Chemical S, 2,6-bis(4-methyl-alpha-aminobenzyl)pyridine, from 2,6-pyridinedicarboxylic aciddichloride and toluene, and its structure was confirmed by infraredanalysis,

EXAMPLE 20 Method 3 was used to prepare Chemical T, 2,5-bis(4-methyl-alpha-aminobenzyl)pyridine, from 2,5-pyridinedicarboxylic aciddichloride and toluene, and its structure was confirmed by infraredanalysis.

12 EXAMPLE 21 This example illustrates the effectiveness of thepresently employed chemicals as bactericides.

Thirty-five milligrams (or less, to provide the concentrations indicatedin Table I, below) of chemical is dissolved in 5 ml. acetone to which 45ml. of a 0.01% aqueous solution of a wetting agent (e.g.,isooctylphenylpolyethoxyethanol, Triton X-100) is added. Three ml. ofthis preparation is pipetted into a 50 ml. Erlenmeyer flask containing 5ml. nutrient agar and kept liquefied at 48. The bacterial inoculum (0.25ml.) consisting of a cell suspension of Escherichia coli orStaphylococcus aureus is then added to the nutrient-chemical preparationin each flask. Thus each flask contains a chemical concentration of 255p.p.m. or less. The nutrient-chemical-bacterial mixture is poured into 2/2 inch plastic Petri dishes, allowed to harden and incubated at 30.Observations for growth are made at 24, 48, 72 and 168 hours. Thechemical treatments are compared with an untreated, inoculated controlusing a bacterial growth evaluation of growth or no growth. The resultsare exemplified by the 48 hour inspection as shown in Table I. Theuntreated controls of both bacteria show complete coverage of the agarplate surface with bacterial colonies at the time of the 24 hourreading. The data in Table I indicate that these chemicals are effectivebactericides against a broad spectrum of bacteria such as theGram-positive type St. aureus as Well as the Gram-negative type E. coli.

TABLE I [Bacterial growth evaluation: Lowest serial dilution efiectiveto produce no growth after 48 hours incubation] Dilution (p.p.m.)

N0'rE.-N means not tested; I means inefiective at 255 p.p.m.

EXAMPLE 22 This example illustrates the eifectiveness of the pres entlyemployed chemicals as bactericides for water-flood operations insecondary oil recovery. The chemicals are tested against the anaerobicbacterium Desulfovibrio desulfuricans, a deteriorative agent insecondary oil recovery procedures, fuel storage tanks, pipelines, etc.This test is conducted according to the American Petroleum InstituteRecommended Practice for Biological Analysis of Water-Flood InjectionWaters, API- Rp 38, First Edition, May 1959, Section II. In the test,weighed portions of the compounds are dissolved in 10 ml. of acetone andtransferred to ml. of distilled water containing three drops per literof a nonionic surface-active agent (isooctylphenylpolyethoxyethanol)..Aliquots are removed from this stock solution (usually containing 1,000or p.p.m. of chemical) to sterile, screw-capped, clear oneounce bottlessuflicient to obtain a final concentration of 1, 5, 10, 50 and 100p.p.m.

13 To each bottle is added sulfate reducing broth inoculated withDesulfovibrio desulfuricans (1.5%). The recipe for the sulfate reducingbroth is as follows:

The caps are replaced and the bottles incubated at 32- 35 with dailyobservations for one week and weekly observations thereafter for a totalof 4 weeks incubation. An untreated control without added chemical showsheavy growth after 48 hours incubation. The results of the tests at the48 hours observation are shown in Table II.

TABLE II Water-flood operations evaluations lowest concentrationeffective against Desulfovibro desulfuricans This example evaluates thechemicals of this invention as foliage protectant fungicides using thefungus Alternaria solani as the test organism. One gram of the chemicalto be tested is ground with 3 ml. of acetone and 50 mg. of a non-ionicsurface-active agent (isooctylphenylpolyethoxyethanol). The acetone andsurface-active agent are known to be inactive in the biological testrun. The mixture is diluted with water, giving suspensions containing500 to 2000 ppm. of the chemical. These suspensions are sprayed onduplicate six-inch tomato plants (variety Clarks Early Special) using agun-type sprayer which delivers 2.5 ml. per second. The plants are thenplaced in the greenhouse, together with untreated check plants.Twenty-four hours later the treated and untreated check plants areinoculated with a suspension of Alternaria solani spores by means of a20second spray from an atomizer sprayer (delivery rate 1 ml. persecond). The plants are then kept overnight in a control chamber at atemperature of 23 .9 and 100% relative humidity. In the morning theplants are transferred to the greenhouse. Three days later the diseaseis scored by comparing the number of disease lesions of the treatedplants with the untreated check.

The formula to determine percent control is:

= percent control The results are shown in Table III.

TABLE III [Foliage protestant fungicidal spray evaluation against tomatoearly blight (Alternaria aolam')] Percent disease control EXAMPLE 24This example evaluates the chemicals of this invention as antimicrobialagents for the preservation of petroleum hydrocarbons. The test isconducted essentially as outlined in Proposed Procedures for theScreening of Microbial Inhibitors in Hydrocarbon Water Systems, Societyfor Industrial Microbiology Special Publication number 2, pages 3-4.

Ten ml. of sterile Bushnell-Haas solution is dispensed in sterile 25 x150 mm. screw cap test tubes. An overlay of 10 ml. of jet fuel (JP-4),sterile, is added to give a 1.1 ratio of hydrocarbon to Bushnell-Haassolution. The test compound is added to the hydrocarbon or water phasedepending on the solubility of the test chemical, at concentrations fromto 1,000 ppm. The test organisms are added to the tubes in 0.1 ml.amounts (Pseudomonas aeruginosa and Cladosporium resinae). The testtubes are incubated at 25 for 14-28 days with daily agitation andobservations for growth. Weekly streak plates are made onTryptone-glucose extract (TGE) agar and Sabouraud dextrose agar forconfirmation of growth. The test media formulations are as follows:

TEST MEDIA FORMULATIONS Gram/liter distilled H 0 (1) Bushnell-Haasmedium (pH 6.8-7.0):

Magnesium sulfate (MgSO -7H O) 0.20

Calcium chloride (CaCI- 0.02

Potassium phosphate, monobasic (KH PO 1.00

Ammonium nitrate (NH NO 1.00

Potassium phosphate, dibasic (K HPO 1.00

Ferric chloride (FeCl 60% aqueous sol. (2

drops).

(2) TGE agar (pH 6.8-7.0):

The results, as shown in Table IV, are recorded as no growth (0), traceof growth (T), or growth TABLE IV [Preservation of petroleumhydrocarbons against bacteria and fungi:

3 week growth evaluation in jet fuel] Bacteria. Fungi Concentration(p.p.m.) 1,000 500 100 1,000 500 100 Chemical:

A O 0 0 0 0 0 T 0 0 0 T T 0 0 0 0 0 0 0 EXAMPLE 25 TABLE V Chemical AInhibiting concen- Test Organism: tration (p.p.m.)

Candida albicans 500 Streptococcus pyogenes Trichophyton mentagrophytes200 We claim:

1. A method of controlling bacteria or fungi which comprises applying toa locus subject to attack by said bacteria or fungi a bactericidally orfungicidally effective amount of a chemical having the formula:

wherein X is O(CH O wherein n is from 2 to 4, and R and R are the sameor different and are selected from the group consisting of hydrogen,methyl, methoxy, and phenoxy.

2. The method of claim 1 in which the organisms being controlled arebacteria.

3. The method of claim 2 in which the said chemical is 1,2 bis[4 (3methyl-alpha-aminobenzyl)phenoxy] ethane.

4. The method of claim 2 in which the said chemical is 1,3-bis [4-(alpha-aminobenzyl phenoxy] propane.

5. The method of claim 2 in which the said chemical is 1,4-bis [4-(alpha-aminob enzyl phenoxy] butane.

6. The method of claim 1 in which the organisms being controlled arefungi and the locus to which the chemical is applied is plant life.

7. The method of claim 6 in which the said chemical is 1,2 bis[4 (3methyl-alpha-aminobenzyl)phenoxy] ethane.

8. The method of claim 6 in which the said chemical is 1,3-bis [4-alpha-aminobenzyl phenoxy] propane.

9. The method of claim 6 in which the said chemical is1,4-bis[4-(alpha-aminobenzyl)phenoxy]butane.

References Cited UNITED STATES PATENTS 3,663,712 5/1972 Schmeling et al.424-330 ALBERT T. MEYERS, Primary Examiner A. J. ROBINSON, AssistantExaminer US. Cl. X.R.

